Research Summary

The general goal of our research is to understand how the kidney regulates the composition of the urine, especially as needed to maintain the salt (NaCl) and acid-base balance of the body. To eliminate waste products from the body, the kidney filters gigantic quantities of the plasma (over 160 quarts per day) resulting in the flow of huge quantities of water, NaCl and the base bicarbonate through the renal tubules. The first portion of each renal tubule is called the proximal tubule, and the proximal tubules are collectively responsible for reabsorbing the vast majority of the filtered NaCl, bicarbonate and water, and secreting acid in the form of ammonium ions.

Our lab has specifically focused on identifying the proteins involved in mediating the transport of bicarbonate, NaCl and ammonium in the proximal tubule. We found that “knockout” mice lacking one of these transport proteins have a high incidence of calcium oxalate urinary stones, the same type that is most common in human patients with kidney stones. We showed that the cause of the calcium oxalate kidney stones is a very high concentration of oxalate in the urine. We found that this kidney transport protein also plays a very crucial role in the intestine, where it secretes oxalate and thereby limits how much of ingested oxalate is absorbed and then excreted in the urine. Based on this discovery, our laboratory has been devoting increasing effort to understanding the role of transporters in governing oxalate homeostasis and excretion. We have also been studying mechanisms by which oxalate crystals induce inflammation and thereby cause damage to the kidney and other tissues.

Extensive Research Description

Our general goal is to characterize the mechanisms regulating sodium, acid-base, and anion excretion by the kidney. Our work is primarily focused on membrane transport proteins mediating ion exchange, namely NHE isoforms mediating Na+-H+ exchange, and SLC26 isoforms mediating anion exchange. One approach involves the generation of isoform- and phospho-specific polyclonal and monoclonal antibodies to identify the cellular and subcellular sites of expression of ion exchangers in the kidney and other tissues, and to study their regulation. A complementary approach uses mice with targeted gene disruption to elucidate the physiological roles of ion exchangers and associated proteins under in vivo conditions. For example, work with mice lacking anion exchanger Slc26a6, which can function as an oxalate transporter, revealed a phenotype of calcium oxalate kidney stones. This finding in turn has motivated studies on the mechanisms and regulation of oxalate transporters and their roles in oxalate homeostasis, urolithiasis, and crystal-induced inflammation and kidney disease.